Evidence that gamma-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-kappa B-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

    Authors

    T. V. Arumugam; Y. L. Cheng; Y. Choi; Y. H. Choi; S. Yang; Y. K. Yun; J. S. Park; D. K. Yang; J. Thundyil; M. Gelderblom; V. T. Karamyan; S. C. Tang; S. L. Chan; T. Magnus; C. G. Sobey;D. G. Jo

    Comments

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    Abbreviated Journal Title

    Mol. Pharmacol.

    Keywords

    FACTOR-KAPPA-B; CEREBRAL-ARTERY OCCLUSION; ALZHEIMERS-DISEASE; TRANSCRIPTION FACTOR; SYNAPTIC PLASTICITY; FOCAL ISCHEMIA; BRAIN-INJURY; MODEL; ACTIVATION; MECHANISMS; Pharmacology & Pharmacy

    Abstract

    Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the gamma-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, gamma-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-kappa B (NF-kappa B), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a gamma-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, gamma-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-kappa B, pro-death protein Bim, and caspase pathways.

    Journal Title

    Molecular Pharmacology

    Volume

    80

    Issue/Number

    1

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    23

    Last Page

    31

    WOS Identifier

    WOS:000291717000003

    ISSN

    0026-895X

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